Towards the Application of Purely Inorganic Icosahedral Boron Clusters in Emerging Nanomedicine

Abstract

Traditionally, drugs were obtained by extraction from medicinal plants, but more recently also by organic synthesis. Today, medicinal chemistry continues to focus on organic compounds and the majority of commercially available drugs are organic molecules, which can incorporate nitrogen, oxygen, and halogens, as well as carbon and hydrogen. Aromatic organic compounds that play important roles in biochemistry find numerous applications ranging from drug delivery to nanotechnology or biomarkers. We achieved a major accomplishment by demonstrating experimentally/theoretically that boranes, carboranes, as well as metallabis(dicarbollides), exhibit global 3D aromaticity. Based on the stability-aromaticity relationship, as well as on the progress made in the synthesis of derivatized clusters, we have opened up new applications of boron icosahedral clusters as key components in the field of novel healthcare materials. In this brief review, we present the results obtained at the Laboratory of Inorganic Materials and Catalysis (LMI) of the Institut de Ciència de Materials de Barcelona (ICMAB-CSIC) with icosahedral boron clusters. These 3D geometric shape clusters, the semi-metallic nature of boron and the presence of exo-cluster hydrogen atoms that can interact with biomolecules through non-covalent hydrogen and dihydrogen bonds, play a key role in endowing these compounds with unique properties in largely unexplored (bio)materials.

Keywords: BNCT; COSAN; FESAN; PBFR; PET; SPECT; antimicrobial; bioimaging; carboranes; luminescence; metallabis(dicarbollide); photodinamic therapy (PDT); proton therapy.

Figure 1

Representation of icosahedral borane, carboranes at the top as well as metallabis(dicarbollides) with the schematic representations of the different conformers of the most known metallabis(o-dicarbollide) in the middle and at the bottom, respectively.

Figure 2

Schematic representation of some substituted closo ortho-carboranes at the B vertices (left), at the C vertices (right). Blue circles represent the C atoms, while orange ones the B atoms and white ones are the B atoms or B-H vertices (H atoms omitted for clarity).

Scheme 1

Representation of the Boron Neutron Capture Therapy reaction (BNCT). Blue circles represents protons while yellow ones neutrons.

Figure 3

Neutral carborane clusters (ortho-, meta-, and para-) can be functionalized at B, at C, or at both C and B vertices to achieve water-soluble polyanionic high boron content molecules [62,63,64,65].

Figure 4

(a) Schematic representation of the two components (inhibitors of kinases receptor + icosahedral boron clusters) of the designed hybrid molecules with potential dual action. (b) The newly synthesized neutral and anionic boron clusters, which contain quinazoline molecules with potential dual action (chemotherapy + radiotherapy) result in significant clinical benefits [66,67,68]. The black, circles represents C atoms or C_c-H vertices, the pink circles represent B–H vertices and the purple ones Boron atoms.

Figure 5

Neutral carboranes onto nanoparticles (gold NPs and magnetic NPs) as vehicles for cancer treatment [71,74]. Both families offer the possibility of dual action (photothermaltherapy + BNCT or hyperthermaltherapy + BNCT), which may result in significant clinical benefits [73].

Figure 6

(a) CryoTEM image of glioblastoma A172 cancer cell after carborane-magnetic nanoparticles uptake and proliferation curves of A172 cells re-plated one day after BNCT treatment. BNCT studies were carried out by incubating A172 cells for 24 h with carborane-magnetic nanoparticles (20 μg/mL boron). The amount of internalized boron measured by ICP-MS was 133 ± 25 μg/g, corresponding to a ¹⁰B concentration of 26 ± 5 μg/g [73]. (b) Effect on HT-29-cell survival without or with hybrids or BPA treatment post-neutron-irradiation (1 and 2 Gy). Compounds were studied at doses equivalent to 10.0 ppm of ¹⁰B for 1 h of incubation. (*) p < 0.05; (**) p < 0.01. Reproduced from Ref. [61] with permission from Wiley & Sons.

Figure 7

Schematic representation of (a) the [o-COSAN]⁻ ability to readily cross cell membranes [65] and (b) [o-COSAN]⁻ interaction with DNA [71]. (c) Percentage of viable U87 and T98G cells 24 h after neutron irradiation.

Figure 8

Optical microscopy images of C. elegans. (Top): The embryos and, (bottom): At the L4-stage before (control) and after incubation with Na[8,8′-I₂-o-COSAN] 200 μM [86].

Figure 9

Schematic representation of the in vitro (right) and in vivo (left) studies of Na[o-COSAN] [85].

Figure 10

Imaging experiments by in vivo PET-CT and SPECT-CT with Na[8-I-o-COSAN] after nuclear interchange of I natural by ¹²⁴I and ¹²⁵I, respectively. Reproduced from Ref. [85]. with permission from the Royal Society of Chemistry.

Scheme 2

Isotopic exchange: (a) Between [¹²⁴I]iodide, [¹²⁵I]iodide, and the anionic [8-I-o-COSAN]⁻ cluster, (b) between [¹²⁵I]iodide and the neutral 3-iodo-o-carborane cluster by using Herrmann’s catalyst (the organopalladium compound made by reaction of tris(o-tolyl)phosphine with palladium(II) acetate).

Figure 11

Mössbauer spectrum and 2D elemental maps of Fe distribution indicate that [o-⁵⁷FESAN]⁻ is present inside U87 cells, an important requisite for selective energy deposition by Mössbauer absorption. Reproduced from [88] with permission from the Royal Society of Chemistry.

Scheme 3

Representation of the Proton Boron Fusion Reaction (PBFR). Blue circles represent protons while the yellow ones represent neutrons.

Scheme 4

Graphical representation of the transport of small anionic metallabis(dicarbollide) molecules through microbiological membranes of Candida sp. (left), Gram-positive (center), and Gram-negative (right) [100].

Figure 12

(a) Molecular structures of boron cluster-BODIPY conjugates 1–5 (pink circles in the cluster are B or B-H and black circles in the cluster are C-H. (b) Intracellular localization of BODIPY dyads 1 and 3 in HeLa cells obtained by confocal laser scanning microscopy (left). Cellular uptake comparison between BODIPY dye and BODIPY-boron clusters at 100 µg/mL of B for each compound (CLSM) (left). Mean values and SD from three independent experiments. a.u.: arbitrary units (right). Reprinted (adapted) with permission from Ref. [129] Bioconjugate Chem. 2018, 29, 1763–1773. Copyright 2018, American Chemical Society.

Figure 12

(a) Molecular structures of boron cluster-BODIPY conjugates 1–5 (pink circles in the cluster are B or B-H and black circles in the cluster are C-H. (b) Intracellular localization of BODIPY dyads 1 and 3 in HeLa cells obtained by confocal laser scanning microscopy (left). Cellular uptake comparison between BODIPY dye and BODIPY-boron clusters at 100 µg/mL of B for each compound (CLSM) (left). Mean values and SD from three independent experiments. a.u.: arbitrary units (right). Reprinted (adapted) with permission from Ref. [129] Bioconjugate Chem. 2018, 29, 1763–1773. Copyright 2018, American Chemical Society.

Figure 13

(a) Molecular structures of Tin complexes containing anionic boron clusters 6-9 (pink circles in the cluster are B or B-H, black circles in the cluster are C-H). (b) Cellular uptake of organotin compounds 6 and 8 bearing anionic [B₁₂H₁₂]²⁻ (left) and [o-COSAN]⁻ (right) by confocal laser scanning microscopy (CLSM). The yellow and red arrows show the internalization of our compounds in the cytoplasm and nucleoli [130]. Reprinted/adapted with permission from Ref. [130] Copyright 2018, Wiley.

Figure 13

(a) Molecular structures of Tin complexes containing anionic boron clusters 6-9 (pink circles in the cluster are B or B-H, black circles in the cluster are C-H). (b) Cellular uptake of organotin compounds 6 and 8 bearing anionic [B₁₂H₁₂]²⁻ (left) and [o-COSAN]⁻ (right) by confocal laser scanning microscopy (CLSM). The yellow and red arrows show the internalization of our compounds in the cytoplasm and nucleoli [130]. Reprinted/adapted with permission from Ref. [130] Copyright 2018, Wiley.

Figure 14

Molecular structures of the representative compounds: 10, 11, and 12 (top) ((pink circles in the cluster are B-H and black circles in the cluster are C). Confocal images of 10 μM 12 in live HeLa cells after 30 min incubation: (a) Panels from left to right show the confocal green channel (λ_exc = 486 nm, λ_em = 500 nm), red channel (λ_exc = 535 nm, λ_em = 610 nm), merged and bright channels, respectively. Scale bars represent 10 and 15 µm. (b) z-stack visualization [132]. Reprinted/adapted with permission from Ref. [132] Copyright 2020, Wiley.

Figure 15

Fluorescence intensity emitted by HeLa cells incubated 4 h with 10 µM of diiodinated antracene-m-carborane. Image obtained with the confocal laser scanning microscope [134] (pink circles in the cluster are B-H, black circles in the cluster are C or C-H and blue circles in the cluster are B).

Scheme 5

Synthesis of the graphene oxide covalently bonded to the radiolabeled COSAN (pink circles in the cluster are B or B-H and blue circles in the cluster are C-H). Reprinted/adapted with permission from Ref. [135] Copyright 2021, American Chemical Society.

Figure 16

TEM image of GO-[¹²⁴I]I-COSAN internalized by HeLA cells, C. elegans incubated with GO-[¹²⁴I]I-COSAN and PET images of GO-[¹²⁴I]I-COSAN in the mice at different times (pink circles in the cluster are B or B-H, blue circles in the cluster are C-H and red circles exocluster ar the ¹²⁴I.). Reprinted/adapted with permission from Ref. [135] Copyright 2021, American Chemical Society.

Figure 17

Structures of RuCB, IrCB, RuCB2, and IrCB2 (pink circles in the cluster are B-H and black circles in the cluster are C).

Figure 18

Orthogonal projection of z-stacks of live SKBR-3 cells incubated with 10 µM RuCB, IrCB, RuCB2, or IrCB2 for 4 h and observed under CLSM. (Top row): To analyze the localization of the compounds, fluorescence mode was used. Compound luminescence emission was detected in the range of 614–760 nm (red) by exciting the cells using the λ_ex 405 nm laser. Wheat Germ Agglutinin (WGA) fluorescence emission (membrane) was detected in the range of 496–579 nm (green) by exciting the cells using the λ_ex 488 nm laser. (Bottom row): Magnification of the selected areas (square boxes). Scale bar, 5 µm [136].